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Influenza Virus - Structure, Function, and Taxonomy

Influenza is an important human pathogen that causes a seasonal infection that infects 5-15% of the northern hemisphere each year, causing 2-3 million hopsitalizations and tens of thousands of deaths each year. For this reason, it is very important that humans understand what this disease is and how it functions, so that they may begin to combat the infection and identify ways to subvert the disease before it takes an extreme toll on the human populace. In 1918, a flu epidemic known as the Spanish Flu killed hundreds of millions of people, and there is significant fear that such a pandemic could arise again, driving even more research into flu and its function.

Flu Structure

Flu is a virus - that is, it is a non living mass of self replicating material that may mimic life but lacks the ability to itself reproduce, thus making it not truly alive in this sense. The flu virus is a virus in the family of viruses known as orthomyxoviruses, and it uses RNA nucleic acid as its genetic material (whereas mammals use DNA, with RNA serving as an intermediate species used transiently in our cells). This RNA is split into 8 segments that encode for 11 or 12 viral proteins (versus the tens of thousands of proteins encoded for by human cells). The virus takes the form of a microscopic particle that is a ball of lipids (the material that makes up the walls of your cells - their membranes) coated in specific proteins known as glycoproteins. Each of the proteins encoded by the flu virus has important implications for flu structure and/or function, and as such it is important to understand the identity of each protein.

The NEP Protein

Also known as NS2, this protein is important for controlling the transportation of viral RNA from the nucleus of the cell, where it is made, into the cytoplasm. In the cytoplasm, these vRNA can then be packaged together into new viral particles that are being formed, and only with this nucleic acid can the virus succeed in reproducing.

The M1 Protein

This protein is important for controlling the transportation of viral RNA from the nucleus of the cell, where it is made, into the cytoplasm. In the cytoplasm, these vRNA can then be packaged together into new viral particles that are being formed, and only with this nucleic acid can the virus succeed in reproducing. The M1 protein is also involved in forming the protein capsid of the virus, coordinating the structure of the virus by binding to surface proteins just under the viral surface and ensuring that they are properly oriented.

The PB1 Protein

This protein is a part of the viral polymerase complex that is necessary for the virus to produce more copies of its RNA. Normally cells in your body will produce RNA, as viruses do, but in order to do so they need a DNA template from which to create RNA copies. Since the flu virus does not express DNA, cellular polymerases cannot create new copies of the flu genome and it must thus bring its own polymerase into the nucleus, where it can replicate the flu genome. This protein is coiled along with the rest of the viral polymerase and the viral RNA inside of packaged viral particles.

The PB2 Protein

This protein is a part of the viral polymerase complex that is necessary for the virus to produce more copies of its RNA. Normally cells in your body will produce RNA, as viruses do, but in order to do so they need a DNA template from which to create RNA copies. Since the flu virus does not express DNA, cellular polymerases cannot create new copies of the flu genome and it must thus bring its own polymerase into the nucleus, where it can replicate the flu genome. This protein is coiled along with the rest of the viral polymerase and the viral RNA inside of packaged viral particles. This protein also has additional functions that allow it to assist the PA protein (see below) in its “cap snatching” behavior that protects viral RNA from degradation by host cells.

The PA Protein

This protein is a part of the viral polymerase complex that is necessary for the virus to produce more copies of its RNA. Normally cells in your body will produce RNA, as viruses do, but in order to do so they need a DNA template from which to create RNA copies. Since the flu virus does not express DNA, cellular polymerases cannot create new copies of the flu genome and it must thus bring its own polymerase into the nucleus, where it can replicate the flu genome. This protein is coiled along with the rest of the viral polymerase and the viral RNA inside of packaged viral particles. This protein also contains an endonuclease domain that targets host immature mRNAs in the nucleus, when they are held in place by the PB2 domain. PA cleaves a special structure called the 5' cap off of these pre-RNAs, allowing it to be attached instead to viral RNAs. This is important because host cells can usually tell the difference between their own RNA and viral RNA, allowing them to degrade only viral RNA. These caps signal that an RNA is of self origin, however, so the viral cap snatching behavior is quite advantageous.

The NP Protein

This protein is important for the packaging of the viral RNA into new viral particles, and for maintaining it in a stable state. Human DNA is generally organized by wrapping it around proteins known as histones that keep it compact and regulate the ability of other molecules to access the DNA. In the same way, viral RNA coils around NP proteins (and it also binds polymerase subunits), protecting it and allowing it to form into new viral particles.

The M2 Protein

This protein is expressed on the surface of the flu viral particles, and it forms a small channel through the membrane of the virus. The channel is tetrameric in nature, and is a type 3 transmembrane structure. This channel, when it enters into the endosome of a cell being infected by the virus, is activated by the acidity of the invaded environment, which allows acidic ions to pass through and enter into the core of the viral particle. This acidification of the viral core is critical for the release of viral RNA into the cytoplasm of the host cell, and without this acidification release will be impaired, which would make the viral replications cycle very likely to fail. When this protein is newly formed, it passes through the Golgi complex inside an infected cell, and while it does so it remains open, acidifying the Gogli. The body interprets this acidification of the Golgi as a danger signal and activates an inflammatory pathway that alerts other cells to the presence of a flu infected cell. This is but one of several ways that cells sense and respond to influenza.

The Hemagglutinin Protein

Also known as HA, hemagglutinin is a flu protein with which many people are familiar in a sense - it is commonly used to classify types of flu virus, as it is the “H” in H5N1 or H1N1 flu virus. This classification does not capture the entirety of variation in flu viruses, but it is useful for grouping viruses based on shared origins and characteristics. Hemagglutinin is expressed on the surface of flu viral particles, and it is essential for their entry into the cells that they infect. It serves as a way by which the virus binds receptors on the surface of the cells it aims to infect, thus allowing the virus to be taken into the cell wherein it can begin its infectious cycle. If HA activity is inhibited, or if the cell lacks the kind of receptor that is normally bound by HA, then the virus will not be able to enter into that cell and thus the viral life cycle will not be able to begin anew.

The Neuraminidase Protein

Also known as NA, neuraminidase is a flu protein with which many people are familiar in a sense - it is commonly used to classify types of flu virus, as it is the “N” in H5N1 or H1N1 flu virus. This classification does not capture the entirety of variation in flu viruses, but it is useful for grouping viruses based on shared origins and characteristics. The neuraminidase protein is present on the surface of the flu virus, and it is essential for allowing the flu to spread from cell to cell. While hemagglutinin may allow flu to bind to the cells it is infecting, newly formed viral particles express lots of hemagglutinin that would make them stick to the same cell they are trying to leave. It is thus the job of neuraminidase to cleave the virus receptors on the surface of the cell, thus allowing the virus to escape so it can go infect other cells. If neuraminidase activity is inhibited, then the viral particles will fail to escape and will form large aggregates at the surface of the infected cell.

The PB1-F2 Protein

This protein, along with the NS1 protein, seems to control many of the activities that antagonize normal host processes in such a way as to improve viral replication. This protein is unique in that not all strains of flu express it unlike the other proteins mentioned herein. In infected cells, this protein localizes to the mitochondria and disrupts their membrane polarization, which is important for their function and thus for cellular energy production and detection of intracellular viruses - two processes that both require the mitochondria to work properly. This disruptions seems to promote the death of the cell in which it is active, which releases viral particles so that they can go off to infect more cells, thus promoting viral spread more rapidly. Expression of the PB1-F2 protein in a flu virus is correlated with the ability of that virus to cause severe secondary bacterial pneumonia after the initial flu infection - a severe complication that is a major cause of death in flu infected individuals. This ensures that study of the function and control of the PB1-F2 protein will be very important in the coming years.

The NS1 Protein

As with the PB1-F2 protein, NS1 is a protein that primarily seems to antagonize normal host cell functions so that the virus may grow and replicate more successfully. Different strains of virus seem to have different types of NS1 with different activities that may yield unique viral benefits in certain hosts. NS1 can redirect host RNA splicing proteins to the nucleus of an infected cell, where it will splice influenza RNA to produce alternative variants of flu proteins, such as the PB1-F2 protein, thereby enhancing viral pathogenesis. Additionally, NS1 may interfere with normal host mRNA export from the nucleus so that flu mRNA can preferentially escape the nucleus. NS1 also binds to cytosolic sensor proteins that normally detect the presence of viral RNA and warn the cell that there is an infection in progress, allowing NS1 to short circuit this warning system. NS1 further antagonizes activation of signaling components necessary for cells to respond to viral infection, and it imposes a block on protein production in infected cells that is somehow overcome by viral RNAs. With so many varied and potent roles in promoting viral success and replication, study of differences in NS1 function in the coming years will likely yield important insights into how different strains of flu virus are able to infect their hosts.

The N40 Protein

This protein was only recently discovered, and it is encoded by the same segment of the viral RNA that encodes the PB1 protein. What this protein does is not currently well understood, however future research will no doubt reveal an interesting role for N40 in viral infection.

The Flu Life Cycle

As with any life form (or whatever you would like to call flu, as most would agree that a virus is not truly alive in a traditional sense), the influenza virus needs to be able to produce new viral offspring in order to allow it to persist and spread. This production of viral progeny occurs when the flu virus infects the cells of the organism it is infecting. In humans, flu viruses will primarily infect cells of the respiratory tract epithelium. Whether it infects cells of the upper respiratory tract or the lower respiratory tract depends on the structure of the hemagglutinin protein on the surface of the flu virus, which will bind the receptors containing specific sugar linked residues known as sialic acid. Most seasonal flu viruses bind to sialic acid residues found only in the upper respiratory tract. In contrast, the more severe avian bird flu strains that are often mentioned on the news bind sialic acids in the lower respiratory tract. This ensures that avian flu can do more extensive damage to human airways due to the disruption of cells in the lower respiratory tract that are necessary for proper gas exchange. In pigs and birds, however, there sialic acid residues are located mainly in the intestinal epithelium, and as a result flu in these animals will often present more as a GI illness rather than a respiratory one.

To begin the flu life cycle, hemagglutinin binds to these sialic acid containing receptors, which triggers certain intracellular signalling events that tell the cell to take in the receptor and the attached virus as part of a sort of “eat me” signal from the virus. The compartment into which the viral particle is taken is known as an endosome, and the cell uses this compartment to degrade and sort extracellular component be creating an acidic environment that disrupts normal protein function. The flu virus, however, has evolved to take advantage of this acidic environment. Acidification of the endosome opens the M2 ion channel, which then begins pumping acidic ions into the core of the virus which is essential for viral uncoating and viral RNA release. In addition, this acidification cleaves the hemagglutinin protein into two parts, revealing a segment known as the fusion protein, which inserts itself into the wall of the endosome. By doing so, hemagglutinin pulls the flu membrane and the endosomal membrane, which are both made of lipids, together, causing them to fuse together. This process releases the viral RNA and proteins into the cytoplasm of the newly infected cell.

As the viral RNA is transcribed in the nucleus and not in the cytoplasm, the NP, PA, PB1, and PB2 poteins target themselves to the cell nucleus using cellular nuclear import machinery, taking the viral RNA along with them. Viral negative sense genomes are transcribed into three types of RNA molecules by the viral RNA dependent polymerase complex (PB1, PB2, PA): positive sence +cRNA is used as a template to generate more negative sense viral RNA; negative sense small viral RNA (svRNA) that seem to be involved in targetting the viral polymerase and regulating its switch from viral transcription (mRNA production) to replication (vRNA production/export); viral mRNAs (which contain poly-A tails, but only obtain a 5' methylated cap through cap snatching activity) are exported to the cytoplasm for translation. Alternative splicing of viral genome segments encoding multiple proteins is accomplished due to sequestration of host splicing machinery to the nucleus by the NS1 protein, allowing for the production of more proteins than the virus has RNA segments (8 vs. 11-12 proteins).

Viral mRNA are translated in the cytoplasm, and viral proteins required for replication are translocated back to the nucleus via nuclear localization activity. Negative sense vRNA binds polymerase subunits to form vRNPs, which then bind to the M1 and NEP (NS2) proteins in the nucleus, allowing for export to the cytoplasm. Viral HA, NA, and M2 are all transported to the surface of the infected cell through the Golgi compartment, which is important as these proteins need to be on the lipid surface of the newly formed viral particles. Along the way, the M2 protein acidifies the Golgi, alerting the cell to the presence of infection. The M1 protein and the tail end of the M2 protein are important for viral packaging and budding, allowing for the assembly of new virions at sites of cell surface M2, HA, and NA proteins; the specific packaging model of vRNA packaging is currently favored over a random model of packaging due to targeting sequences on vRNAs.

These newly assembled protein clusters and vRNA structures at the cell surface bud out, stealing membrane material from the host cell to serve as the viral lipid membrane containing the viral HA, NA, and M2 proteins (and with all the other viral proteins and vRNA inside the virus). All that remains is for NA to cleave sialic acid residues on the surface of the cell, so that HA does not keep the viral particle contained at the surface of the cell that gave birth to it. Once NA has done its work, the new viral particle will be released, allowing it to go off and infect other nearby or distant cells, continuing the viral life cycle. After a time, the infected cell will generally die, causing much of the damage and inflammation associated with flu infection. Some cells may be able to restrain viral spread, however actions of proteins such as PB1-F2 and NS1 provide the virus with potent activities that oppose the normal means by which the host detects that they are infected with a virus. Indeed, in a sense viral evolution and host evolution are something of a molecular arms race, with each species working to subvert the other in a continual quest for persistence and survival.

The Origin of New Flu Strains

While it is impossible to determine with absolute certainty where a strain of virus comes from, there has been great progress made of late on tools that allow scientists to trace the origin of viruses, and from these studies we have learned much about how flu spreads and enters the human population from other species. While it is impossible to determine with absolute certainty where a strain of virus comes from, there has been great progress made of late on tools that allow scientists to trace the origin of viruses, and from these studies we have learned much about how flu spreads and enters the human population from other species. As mentioned above, different flu strains are often classified in part based on the types of HA and NA proteins they have on their surfaces, as these are both the most easily accessible molecules on the virus and the most important for determining what kinds of cells can be infected by the virus. In total there are 16 different types of HA (H1 through H16), and 9 types of NA (N1 through N9). Most of these types, however, do not circulate in the human population, as we are not the native hosts for most flu viruses - no, flu seems to be an infection most common to birds, as well as pigs and horses.

Each year, different flu strains will circulate in the human population. Typically the new dominant strain each year will be similar to the dominant strain in previous years - usually, it will have mutated slightly through the process of antigenic drift. This process ensures that the virus is functionally similar to the previous year's viral strain, but different enough for the immune system to fail to recognize it, thus requiring a new vaccination to protect you from infection. For example, since the 1950's, H3N2 strains have been circulating through the human population and they typically only undergo small changes from year to year, rather than more massive changes. However, when two different flu viruses infect a single cell, they can exchange genetic material in a way that creates an entirely new and potentially dealy strain of flu virus. This is because the flu has a segmented genome with 8 distinct RNA segments, so a cell infected with two different flu strains would be able to create new viral particles with any combination of the RNA from the two viral particles. For example, if a cell were infected with an H1N1 flu virus and an H3N2 flu virus, then offspring viruses could have the surface markers H1N1, H1N2, H3N1, or H3N2 (in theory; some viruses would likely not be stable or able to function well). This process is known as antigenic shift or genomic reassortment.

Reassortment is believed to be a major source of the pandemic strains of influenza, along with infections from other animal species in a process known as zoonotic infection. In the case of reassortment, a newly produced virus strain from a dually infected cell may have a unique mixture of components that allow it to rapidly or robustly induce infection causing more damage than either of the viral particles that gave birth to it. In the case of zoonotic infections, an animal strain of flu from birds or pigs will mutate in such a way as to infect human cells, potentially introducing entirely new flu structural types into the human population with devastating effect. Avian flu strains such as H5N1, for example, are able to infect cells of the lower respiratory tract more effectively than normal circulating flu strains, and as a result they are better able to cause pneumonia and death. Similarly, the recent swine flu pandemic arose suddenly and unexpectedly from a pig source, resulting in a much larger number of cases than typical seasonal strains of flu. Fortunately, that pandemic proved to be contagious but not overly pathogenic, so the number of deaths was not devastating as it has been in past cases of flu pandemics such as the 1918 Spanish flu outbreak mentioned about (also an H1N1 strain).

Birds and pigs seem to be the main animals in which different flu strains mix together through the reassortment process, likely because these species are better able to tolerate influenza infection than are humans. This is because for these animals influenza is a GI infecting virus rather than a respiratory virus, and the GI tract is often more resilient. Birds especially seem to be involved in the spread of virus, as migratory waterfowl populations allow for the virus to move from one location to another, likely initiating spread of the flu from one region to the next. Pigs also serve as ideal mixing sites for flu virus classes, because their cells express both types of sialic acid used by mammalian and bird flu strains to enter cells. This means that in pig cells bird strains of influenza can reassort with mammalian strains, allowing for the production of a novel and deadly swine origin influenza virus. Prior to the 2009 swine flu outbreak, epidemiologists had been aware of the dangers posed by migratory birds, and so there were efforts under way to monitor these populations for new and prominent flu strains. No one expected pigs to prove to be the next source of a pandemic virus, however, demonstrating a clear flaw in the plan. as such, new efforts are now in place to monitor all species that might give rise to the next flu pandemic strain before it actually comes into existance.

Currently, there are only two classes of flu viruses circulating regularly in the human population - H1N1 and H3N2. The H1N1 strain was the dominant strain in the 2014 flu season, and it was in fact the same H1N1 of swine origin that cause a pandemic outbreak in 2009. Other flu strains spontaneously infect people from time to time, as in the case of avian flu strain like H5N1, and when they do so they are often lethal. Thus far, however, there has not been any rapid spread of these avian flu strains from person to person, thus preventing a pandemic outbreak. Even so, constant monitoring of possible sources of flu including migratory birds and pig populations is being maintained in order to allow researchers to predict and hopefully prevent the next flu pandemic outbreak of flu before it has a chance to occur.

Flu Treatments

At present there are two main classes of drugs on the market that are intended to target and treat flu - M2 inhibitors and neuraminidase inhibitors. The most prominent such drug is Tamiflu, which is an NA inhibitor, and it is stockpiled by governments around the world in case there is ever a global flu pandemic. The efficacy of Tamiflu, however, has recently been called into question. Reports suggest that pharma companies suppressed negative data during drug trials, thus making it appear as though Tamiflu was able to reduce the duration of flu infection even though it can not really do so. The issue remains controversial and may not be resolved for some time, however even if Tamiflu is effective it only slightly reduces the severity of flu infection and is not even close to a final solution to the Influenza problem. Perhaps future inhibitors of other influenza proteins such as the M2 or NS1 proteins will have better success are reducing the severity of viral infection and sequelae .

In the meantime, influenza vaccination is currently the best available means of controlling flu spread. Flu vaccines are taken annually, as new flu strains emerge each year and old vaccines will often not protect against these new strains. In addition, the vaccine is of limited duration so it is important for the immune system to receive a boost of the flu vaccine every year. At the moment the vaccine is not overly effective (as opposed to vaccines against other diseases such as Polio or Smallpox), which may explain why this disease is still such a major healt h concern. As such, many labs are currently trying to develop a long lasting and universal flu vaccine. If this is done successfully, then it will allow a person to take a single flu vaccine as a child and be protected throughout their lives. Given the complexity of the flu life cycle and its constant evolution and antigenic switching, such a universal vaccine may be many years down the road, but it will fundamentally alter the course of human health and disease and will no doubt save millions of lives and billions of lives in the long run.

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